Project Abstract Neoadjuvant chemotherapy (NAC) is the standard of care for treatment of locally advanced breast cancer (LABC). Application of this systematic therapy before surgery benefits patients by providing improved rates of breast-conserving surgery, early indication of response to chemotherapy, as well as improved outcomes for certain subgroups of high-risk patients. The clinical response to NAC is correlated with the pathologic outcome at the time of surgery and post-surgery survival. Also, it is important to identify non-responders early in the course of treatment to save them from unnecessary cost and side effects of ineffective treatment, such as nausea, alopecia, haematological toxicity, neurotoxicity (e.g. taxanes) or cardiotoxicity (e.g. anthracyclines). It has also been reported that survival of patients not responding to an initial neoadjuvant regimen, but responding to a different second neoadjuvant regimen is similar to the survival of responders to the initial regimen. Thus, early assessment of breast cancer response to NAC can improve patients' survival by allowing for earlier therapy modification, and potentially accelerating the timeline to administration of an effective NAC. The biggest challenge in monitoring NAC is to quantify response at an early stage of therapy. Response assessment currently relies on tumor shrinkage, but the tumor size changes, i.e. morphologic changes, can happen later than functional and physiologic changes. Thus, new functional assessments need to be explored to improve the accuracy of early therapy response prediction. Interstitial fluid pressure (IFP) has been suggested as a factor affecting therapeutic response. Increased IFP prevents an effective uptake of therapeutic agents and reduces the efficacy of cancer therapy. The IFP of breast tumors can be directly measured invasively using a wick-in- needle technique. However, this invasive method is difficult to apply in patients and not standard of care. Our group has proposed an innovative ultrasound technique called subharmonic-aided pressure estimation (SHAPE) for noninvasive IFP evaluation and recently conducted a pilot study of 3D SHAPE's ability to monitor treatment response in women undergoing NAC. This study showed that the subharmonic signal difference in the tumor relative to the normal tissue could predict treatment response as early as after administration of only 10% of therapy regimen (i.e., 1 cycle of NAC). While encouraging, this study was based on a limited number of cases at a single institution. In this project we propose to bring together researchers from academia and industry in order to conduct a multi-center clinical evaluation to validate previous findings. Our hypothesis is that the subharmonic signal difference in the tumor relative to the normal tissue can predict breast cancer NAC response after 10% of therapy regimen.